Candida-associated denture stomatitis (CADS) is a common, recurring disease among denture wearers and can lead to other oral health problems, systemic infections, compromised quality of life, and even death. Thus far, there are no effective treatment strategies to control CADS, particularly for the elderly veteran population who are often immunologically and/or medically compromised. This project will develop a rechargeable, click-on/click-off anticandidal technology to manage CADS. We propose that methacrylic acid (MAA) moieties can be incorporated into denture materials and act as a rechargeable battery to bind and then slowly release antifungal drugs. Our preliminary studies have demonstrated that MAA (up to 10%) can be copolymerized with denture resin monomers in the curing step without negatively affecting the physical/mechanical properties of the resulting resins. Antifungal drugs such as miconazole and chlorhexidine digluconate can be charged into the new denture materials and slowly released for a prolonged period of time (weeks or months). The drugs could be quenched (washed out or clicked off) by treating the denture materials with a quenching agent such as EDTA, and the quenched denture materials can be recharged with the same or different antifungal reagents. In the current proposal, we will test the hypothesis that this technique can be applied to both urethane-based and acrylic-based denture materials with three anticandidal drugs of different chemical and biochemical structures, i.e., a azole (miconazole), a polyene (nystatin) and a salivary antimicrobial polypeptide (synthetic histatin 5). The specific aims of the proposed research are to: (1) fabricate new acrylic and urethane rechargeable anticandidal denture materials, and characterize the physical/mechanical properties of the new materials, (2) formulate the anticandidal drug-containing denture materials, establish drug binding/releasing kinetics, and evaluate the click-on/click-off anticandidal technology of the new denture materials, and (3) evaluate in vitro the biocompatibility and anticandidal activity of the new denture materials and the risk of microbial resistance to the materials. The evaluation of biocompatibility and anticandidal efficacy of the new systems will be performed in vitro with human oral epithelium-Candida and reconstituted human epithelium (RHE)-Candida co-culture models. The potential risk of developing microbial resistance will also be tested to determine the safety of the new approach. The rechargeable, click-on/click-off anticandidal denture materials developed in this project can activate and terminate antifungal drug treatment depending on the presence or absence of clinical Candida infection. The rechargeable feature will likely allow switching to more potent/effective reagents to enhance anticandidal potency and/or minimize the risk of fungal resistance, leading to a personalized therapeutic strategy for CADS and other related diseases. Furthermore, this new technology could be potentially used in a broad range of drug delivery systems for other oral or systemic diseases and/or infection control of dental/medical devices.